Irrational exuberance might not be the sole domain of streets Broad and Wall. Speculation in AIDS futures has also seen quite a run over the past 18 months. While both seem to be rooted in unseemly corporate profitability, the latter wave of euphoria appears to have begun to cede to a harsh and tenacious reality (if not yet to the full enormity of the therapeutic and funding crises ahead.) And as the pendulum begins its inexorable swing back to a more sober state of affairs (see Nightline, July 25, 1997 as well as the front page of The New York Times, August 22, 1997), Gregg Gonsalves offers his view of "The State of AIDS," which he first delivered at a D.C. forum sponsored by the AIDS Action Council this past July.
We've all heard virologic success stories like this in the press over the past year. Today, however, I would like to focus on the caveats about these triple and quadruple combination regimens -- and their failure to offer significant hope for hundreds of thousands of people with HIV infection. For the past 18 months, our expectations and our public policy have been driven by a giddy optimism. It's now time though, I'm afraid, to remove the rose-colored glasses and face the real challenges that lie ahead.
The new intensive treatment strategies, now known as highly active antiretroviral therapy (or HAART), are indeed remarkably successful in suppressing viral replication in patients with little history of taking anti-HIV medications. Thousands and thousands of HIV+ individuals, however, (including many of my friends who have been infected for more than a couple of years) have listened to the prevailing medical wisdom of years past and taken AZT, ddI and ddC, combined these drugs or added 3TC or d4T. Many later took saquinavir, the grossly impotent but deftly marketed protease inhibitor when it was the first of its class of drugs commercially available in the fall and winter of 1995. The result: thousands of HIV+ individuals are resistant to many of the component drugs in the triple combinations that have shown so much promise in patients naïve to antiretroviral therapy. If they have developed protease inhibitor cross-resistance from earlier saquinavir use, the newer and more potent protease inhibitors, ritonavir, indinavir and nelfinavir are of limited use to them. If they haven't developed protease cross-resistance, but are resistant to AZT and its cousins, they will likely get some benefit from the use of protease inhibitors, but are essentially using a single agent to control HIV. Monotherapy, even with the most potent protease inhibitor, cannot hold the virus at bay for long.
What do we know about my own chances -- and of people like me -- for beating this virus? I have no detectable virus in my body right now, but even this claim is partly artifactual (for reasons I'll soon explain). No one now believes that even the most successful of these combination regimens is capable of completely shutting down viral replication. The embers may be gray and smoldering, but they continue to burn. What my bloodwork and clinical picture will look like in a year or two from now is anybody's guess. My future depends on several factors. First, if I am to get the most out of the drugs I am taking and want to forestall the development of drug resistance, I will have to maintain a daunting daily medication regimen. I take over two dozen pills a day. In addition, to my antiretroviral therapy, I take a drug to control the debilitating diarrhea caused by the protease inhibitor and a drug to control the esophagitis that sent me to the emergency room this winter. If I miss even a single dose of my pills, I greatly increase the risk of HIV's developing resistance to these agents.
Even if I can take my drugs regularly for the next few years, my future is far from certain. Recently, 3 of the 10 people in my clinical trial found out their virus had broken through, with once "undetectable" plasma HIV levels becoming detectable again and beginning to climb upward. What happened is uncertain, but its clear that being "undetectable" doesn't mean there is no viral replication taking place. In fact, recent studies show that most individuals who are "undetectable" by commercially available assays have detectable levels of virus using the more sensitive assays available in research laboratories. What's more, being "undetectable" by even the most sensitive test still means there are thousands of infected cells in the body. Even in the presence of highly active antiretroviral therapy that's working, we now know that HIV can continue to evolve and develop drug resistance.
Will I too break through on my therapy one day? The pertinent question, it seems, is not if but when. I had a scare a few months ago when the amount of the virus in my blood blipped up to detectable levels and then went back down again. After sequencing the virus from that unsettling episode, my doctors told me there was no evidence I had developed genetic resistance to the drugs I am taking. Because we now know that triple combination therapy can fail without the development of specific drug-resistance mutations, their consoling words left me cold. It is clear that I am playing a game of beat-the-clock with a wily adversary. To throw yet another roadblock in the way of the virus, I am thinking of adding a fourth drug to my already onerous cocktail. If I still cant hold back the virus and break through, I will have few (if any) therapeutic options left. There is almost nothing in the new drug pipeline that isnt cross-resistant to the drugs currently on pharmacy shelves.
Will we ever be able to claim victory over the virus using the drugs we have now? All evidence to date suggests not. Even if I am successful in keeping the virus from replicating inside me, the virus has integrated its DNA into the DNA of many of my T-cells and macrophages and quietly sits waiting for its day in the sun. It will take a long time on therapy -- estimates range from 3 to 6 years -- for the cells harboring viral DNA to be rooted out of my body. Meanwhile, there are places in my body where the drugs cant reach -- particularly the brain -- that act as sanctuary sites for my viral invader. And the clock is ticking. And ticking.
We havent beaten HIV, not by a long shot. We are in the eye of the storm, and that second wall of wind is likely to strike us with all the brutal impact of the first. Yes, weve seen our friends rise from their deathbeds. Miraculously, the disabled returned to work. Weve bought ourselves some time, but we mustnt fool ourselves into thinking the storm has passed. Thats the perilous seduction of the eye. If we craft national policy on AIDS based on this false sense of security -- an idea that the worst of this epidemic is over -- were going to get one hell of a surprise and another hell of a mess to clean up a few years hence.
The twentieth century has been one of incredible hubris when it comes to pestilence. We thought we had beaten common bacterial infections and diseases like tuberculosis through antibiotics, or like malaria through antiparasitic drugs and the destruction of mosquitoes with pesticides. In each of these cases, it is the bug that had the last laugh as it roared back evading our most sophisticated attacks. We can acknowledge the progress we have made in the treatment of HIV infection without succumbing to a premature triumphalism that will eventually undo us. We can take advantage of the virus momentary retreat to fortify ourselves and plan for the next battle. Here are a few that we can do right now:
Since the approval and wide-spread use of protease inhibitors in mid-1996, AIDS clinicians and primary care physicians across the country all insist they are seeing a marked decrease in AIDS-related opportunistic infections (OIs) in their HIV-positive patients. Until now, this was all wonderful yet anecdotal news. At the 23rd AIDS Clinical Trials Group (ACTG) Meeting in Washington, D.C. (July 19-23, 1997), a number of investigators presented epidemiologic data which clearly demonstrate that the rate of most OIs has indeed fallen.
In comparing the 18 months before and after January 1996, however, the data reveal that only 5 of the 11 OIs have decreased significantly: MAC, CMV, KS, wasting, PCP. Decreases in the incidence of cryptococcal meningitis, toxoplasmosis, cryptosporidiosis, and esophageal candidiasis, by contrast, were not significant (although the reductions in meningitis and toxoplasmosis approached significance). Furthermore, the marked and visible decrease in opportunistic infections in Clarks study did not occur until the calendar year 1997 -- even though 3 of the 4 protease inhibitors were approved and available by mid-1996. Is it enough to say that these decreases are solely due to the antiviral effect of triple combination therapy? Might there not be other factors involved, such as increased use MAC prophylaxis, steroid usage or dietary changes for the prevention of wasting, or a change in sexual behavior in order to avoid KSHV and thus Kaposis?
A preliminary data analysis of the OI events in ACTG 320 was presented by USCs Judith Currier, an excellent young investigator whos taking the ACTG by storm. ACTG 320 was Mercks indinavir clinical endpoint study which randomized 1,156 patients with CD4 counts <200 and at a minimum of six months prior AZT therapy to add either 3TC (n=579) or to add both 3TC and indinavir (n=577). To no ones surprise, ACTG 320 was stopped early because of statistically significant differences in deaths and AIDS events favoring the protease inhibitor-containing group. There were 60 OIs in the group that added one drug and 31 OIs in the group that added both 3TC and indinavir. A detailed analysis of the clinical events in ACTG 320 is currently underway (as well as a possible comparative analysis with ACTG 175). Nonetheless, it is probably safe to say that the incidence of OIs in the triple therapy arm of ACTG 320 is the lowest ever documented in a study of this size with this patient population. It will be interesting to see whether or not some of these OIs (i.e., PCP and MAC) developed in individuals on prophylaxis and also at what CD4 count. That is, Did increases in CD4 cell counts protect these individuals from new opportunistic infections?
CD4 cell increases and an "undetectable" viral load are one thing, but this decrease in life-threatening OIs is the proof of the pudding and arguably the reason we are finally seeing a substantial decline in AIDS deaths. Numerous studies have documented the deleterious effect OIs have on HIV-infected persons: the inflammatory cascade where one OI seems to lead directly to another; the independent predictability of at least six OIs to shorter survival; and the well-documented viral load surges which accompany many OIs. So, in the ineradicable mantra of Martha Stewart, this reduction in OIs is "a good thing."
Nevertheless, investigators at the ACTG meeting expressed caution that we are in a "honeymoon phase." Clinical follow-up of ACTG 320 was, after all, less than one year. And widespread use of protease inhibitors has just recently crossed the one year mark. There are many who fear that in 6 to 18 months we might see a substantial number of patients fail their protease inhibitor regimens (because of resistance and noncompliance) and experience anew a marked increase in the incidence of opportunistic infections.
If this is indeed to be the case, only effective OI prophylactic regimens, (TMP-SMX for PCP and clarithromycin or azithromycin for MAC) can insure patients with viral break-through and faltering CD4 cell counts protection from the opportunistic infection menace. Even then, prevention of CMV will remain problematic. Roches outrageously expensive oral ganciclovir (the closest thing we have to a prophylactic against CMV -- whatever happened to lobucavir?) is only truly effective in CMV DNA-PCR-negative patients (that is, those at the lowest risk of developing CMV disease). What are we to do with those high-risk patients with high levels of CMV DNA in their blood? Dont look for any help from Basel. Roche execs are said to be reconsidering the potential market for its oral ganciclovir prodrug (RS-79070) now that the incidence of CMV disease appears to have fallen so. But such a short-sighted business decision would be, well, myopic. Even if this business is all about the bottom line, slowing or discontinuing the development of RS-79070 is (in as little as a year or two from now) very likely to be exposed as strategic miscalculation. Woe to s/he who wields that red pen.